Endothelin is a vasoconstrictive peptide composed of 21 amino acid residues, which was isolated from the culture supernatant of porcine vascular endothelial cells in 1988. This is produced by the processing of an endothelin precursor with an endothelin converting enzyme. Although endothelin is known to be widely produced by the cells of the lungs, intestines, kidneys, pancreas, spleen, heart, eyes, placenta, central nervous system and the like, it is said that endothelin is also produced by many cells other than these cells, such as bronchial epithelial cells, vascular smooth muscle cells and macrophages. As to endothelin, three isopeptides (endohelin-1, endothelin-2 and endothelin-3) are known, and they have a transient vasodilative effect and a subsequent sustained vasoconstrictive effect. Moreover, in addition to their effects on the cardiovascular system, endothelins have a wide variety of effects such as contraction of the airway, intestinal tract and uterine smooth muscle, proliferation of cells, and promotion of aldosterone secretion. It is believed that these effects are achieved through the medium of two subtypes of endothelin receptors (i.e., the endothelin A receptor and the endothelin B receptor). Since an oversecretion of endothelins is considered to be associated with various diseases such as hypertension, ischemic heart diseases, cerebral ischemia, kidney diseases, hepatic dysfunction, arteriosclerosis, and restenosis after percutaneous transluminal coronary angioplasty (i.e., post-PTCA restenosis), compounds having antagonism to endothelin receptors are expected to be effective as remedies for diseases caused by an oversecretion of endothelins.
The conventionally known nonpeptide compounds having antagonism to endothelins include, for example, Bosentan (see EP-A-510526), SB-209670 (see the pamphlet of WO93/8799) and the like. However, these compounds may not be said to be satisfactory.
Moreover, as 4,5-dihydro-[1H]-benz[g]indazole-3-carboxylic acid derivatives, there are known certain 4,5-dihydro-1-phenyl-[1H]-benz[g]indazole-3-carboxylic acids which are substituted by a substituted phenyl group at the 1-position [see J. Heterocyclic Chem., 13, 545 (1976)]. However, neither statement nor suggestion about their antagonism to endothelins is found in this reference.
It has now been found that compounds comprising 4,5-dihydro-[1H]-benz[g]indazole-3-carboxylic acid which is substituted by a 5-pyrimidinylmethoxy group at the 7-position and by a substituted phenylmethyl group at the 1-position have excellent antagonism to endothelin receptors and, moreover, some of these compounds also have an excellent inhibitory effect on phosphodiesterase III.
Thus, the present invention provides 4,5-dihydro-[1H]-benz[g]indazole-3-carboxylic acid derivatives represented by the above formula (I), or their salts.